Tissue Biomarkers in Hepatocellular Tumors: Which, When, and How

Abstract

Few tissue markers are currently available to pathologists in the study of hepatocellular tumors. These markers should be used carefully taking into consideration not only morphology but also, and sometimes even more important, the clinical setting where the lesion to be diagnosed had developed. Glypican-3, heat shock protein 70, and glutamine synthetase (GS) are markers currently used, as a single panel, to discriminate the nature of a <2 cm hepatocellular lesion lacking radiological features of hepatocellular carcinoma (HCC) detected in a cirrhotic patient under surveillance. Their use, which can be improved by clathrin heavy chain, is mostly requested on liver biopsy. Hepatocyte paraffin 1, arginase-1, polyclonal carcinoembryonic antigen, CD10, and bile salt export pump are tissue markers used to confirm, at histology, the diagnosis of HCC made by imaging before enrollment for phase III studies on novel anti-HCC drugs. In this setting, pathologists are usually requested a conclusive diagnosis on a liver biopsy of a poorly differentiated, necrotic, enriched in stem-phenotype, carcinoma. Liver fatty acid-binding protein, serum amyloid A, C-reactive protein, prostaglandin D2 synthetase, GS, and β-catenin can be used either on biopsy or surgical specimen to classify hepatocellular adenoma into hepatocyte nuclear factor (HNF-1α) inactivated (steatotic), inflammatory, with dysregulation of sonic hedgehog and prostaglandin pathways, β-catenin mutated, and unclassified.

Keywords: hepatocellular adenoma; hepatocellular carcinoma; hepatocellular tumors; predictive markers; prognostic markers; tissue markers.

Figure 1

Morphological and immunohistochemical features of a 1.7 cm hepatocellular lesion detected in a cirrhotic patient with imaging not conclusive for malignancy. (A) The lesion is barely seen on the left of the biopsy (H/E, 4×); (B) at higher magnification, it is characterized by cell crowding and not triadal vessels (H/E, 40×); and (C) rare pseudoglands (H/E, 40×). Overall, morphological features are in keeping with a differential diagnosis between HGDN and early/G1 hepatocellular carcinoma (HCC). The lesion, when investigated with the diagnostic panel glypican-3 (GPC3)–heat shock protein 70 (HSP70)–glutamine synthetase (GS) showed (D) a strong GS staining in patchy areas (GS staining, 4×), (E) a focal cytoplasmic staining for GPC3 (GPC3 staining, 40×), and (F) the presence of scattered lesional cells arranged in cluster showing nuclear/cytoplasmic immunoreactivity for HSP70 (HSP70 immunostaining, 40×). All these findings are in keeping with a conclusive diagnosis of early/G1 HCC.

Figure 2

Morpho-phenotypical correlations in the hepatocellular adenomas (HAs). (A,D) This hepatocellular lesion [(A), H/E, 4×, right part of the biopsy] is negative to liver fatty acid-binding protein (LFABP) staining [(D), LFABP staining, 4×] findings consistent with a final diagnosis of HNF-1α inactivated, steatotic, HA; LFABP cytoplasmic positivity is always observed in normal parenchyma. (B,E) This hepatocellular lesion characterized by ectatic sinusoids [(B), H/E, 10×] shows diffuse cytoplasmic immunoreactivity to serum amyloid A (SAA) [(E), SAA immunostaining, 10×], which is diagnostic for an inflammatory (telangiectatic) HA. (C,F) The lesional biopsy [(C), H/E, 4×, upper fragment] obtained from a 3 cm hepatcellular nodule in an 18-year-old man shows a strong and diffuse immunoreactivity to glutamine synthetase (GS); this finding is consistent with a diagnosis of an atypical (β-catenin mutated) adenoma that was further confirmed by nuclear immunoreactivity to β-catenin not shown; note for comparison in the lower fragment the normal GS staining in the perivenular areas.

Figure 3

Algorithmic approach to the use of tissue biomarkers in the clinical setting of small hepatocellular nodules detected in cirrhotic patients under surveillance and in hepatocellular nodules detected in unremarkable liver.